The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Pitavastatin calcium is chemically known as (3R,5S)-7-[2-cyclopropyl-4-(4-flourophenyl)-quinolin-3-yl]-3,5-dihydroxy-6-(E)-heptenoic acid calcium salt having the Formula I is known in the literature.

Pitavastatin is a synthetic lipid-lowering agent that acts as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme a (HMG-CoA) reductase (HMG-CoA Reductase inhibitor). This enzyme catalyzes the conversions of HMG-CoA to mevalonate, inhibitors are commonly referred to as “statins”. Statins are therapeutically effective drugs used for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. Pitavastatin is used in the treatment of hyperchloesterolemia and mixed dyslipidemia.
Pitavastatin calcium has recently been developed as a new chemically synthesized and powerful statin by Kowa Company Ltd, Japan. On the basis of reported data, the potency of pitavastatin is dose-dependent and appears to be equivalent to that of atorvastatin. This new statin is safe and well tolerated in the treatment of patients with hypercholesterolaemia.
Significant interactions with a number of other commonly used drugs can be considered to be extremely low.
Processes for the preparation of pitavastatin are described in EP-A-0304063 and EP-A-1099694 and in the publications by N. Miyachi et al. in Tetrahedron Letters (1993) vol. 34, pages 8267-8270 and by K. Takahashi et al. in Bull. Chem. Soc. Japan (1995) Vol. 68, 2649-2656. These publications describe the synthesis of pitavastatin in great detail but do not describe the hemi-calcium salt of pitavastatin. The publications by LA. Sorbera et al. in Drugs of the Future (1998) vol. 23, pages 847-859 and by M. Suzuki at al. in Bioorganic & Medicinal Chemistry Letters (1999) vol. 9, pages 2977-2982 describe pitavastatin calcium, however, a precise procedure for its preparation is not given. A full synthetic procedure for the preparation of pitavastatin calcium is described in EP-A-0520406. In the process described in this patent, pitavastatin calcium is obtained by precipitation from an aqueous solution as a white crystalline material with a melting point of 190-192° C.
US 2009/0182008 A1 discloses various polymorphic forms A, B, C, D, E, and F, and the amorphous form of pitavastatin calcium salt (2:1). In particular, the crystalline Form A having water content from about 5% to about 15% and process for its preparation are disclosed.
US 2009/0176987 A1 (“the US '987 A1) also discloses polymorphic form crystal form A of pitavastatin calcium which contains from 5 to 15% of water and which shows, in its X-ray powder diffraction as measured by using CuKα radiation, a peak having a relative intensity of more than 25% at a diffraction angle (2θ) of 30.16°.
The US '987 A1 discloses that pitavastatin calcium (Crystal Form-A) when subjected to drying in a usual manner, the crystallinity decreases to a state which is close to an amorphous state and is shown by X-ray powder diffraction pattern as shown in FIG. 2 when the water content becomes about 4%. It is also disclosed that even the crystallinity decreases close to an amorphous state for compound having X-ray powder diffraction pattern as shown in FIG. 1 prior to the drying. It is also disclosed that the stability of crystal Form-A and crystallinity has a very close relationship with respect to water content. Further, it has been reported that the pitavastatin calcium, which has become amorphous, has very poor stability during the storage, as shown in Table. 1.
Table.1 of the US '987 A1 also shows that pitavastatin calcium kept at 40° C. (air tight) has water content of about 7.89 (initial) and 7.81 (after 90 days) with total impurities 0.179 (initial) and 0.211 (after 90 days) with purity of 99.38% (Initial) and 99.64 (after 90 days). Contradictorily, it shows reports that pitavastatin calcium kept in open air has water content of about 7.89 (initial) and 1.77 (after 90 days) with total impurities 0.179 (initial) and 2.099 (after 90 days) with purity of 99.38% (Initial) and 96.49 (after 90 days).
The US '987 A1 also discloses that stability of pitavastatin calcium can be remarkably improved by controlling the water content in the drug substance within a specific range. Also, it reports that there are three types of crystal forms having the same water content range i.e. Crystal Form-A, Crystal Form-B and Crystal Form-C. It has been found that among the three crystalline forms, crystal Form-A is most preferred as a drug substance for pharmaceuticals.
Crystal Form-A is having water content in the range of 5% to 15%, preferably from 9% to 11%. It also discloses that Crystal Form-A is the best as a drug substance for pharmaceuticals.
International (PCT) Publication No. WO 2007/132482 A1 discloses a process for the preparation of pitavastatin calcium by condensing bromide salt of Formula-3 with aldehyde compound of Formula-4 to obtain olefinic compound of Formula-5 and converting olefinic compound to pitavastatin calcium via organic amine salt for purification.
International (PCT) Publication No. WO 2010/089770 A2 discloses a process for the preparation of pitavastatin calcium. WO 2011/089623 A2 discloses alkali or alkaline earth metal salts of pitavastatin.
Polymorphism is defined as the ability of a substance to crystallize in more than one crystal lattice arrangement. Polymorphism can influence many aspects of solid state properties of a drug. Different crystal modifications of a substance may differ considerably from one another in many respects such as their solubility, dissolution rate and finally bioavailability. An exhaustive treatment of polymorphism in pharmaceutical and molecular crystals is given e.g. by Byrn (Byrn, S. R., Pfeiffer, R. R., Stowell, J. G., “Solid-State Chemistry of Drugs”, SSCI Inc., West Lafayette, Ind., 1999), Brittain, H. G., “Polymorphism in Pharmaceutical Solids”, Marcel Decker, Inc., New York, Basel, 1999) or Bernstein (Bernstein, J., “Polymorphism in Molecular Crystals”, Oxford University Press, 2002).
In view of the above, it is therefore, desirable to provide an efficient more economical, less hazardous and eco-friendly process for the preparation of highly pure stable pitavastatin calcium having water content less than 5% wt/wt. The crystalline form provided herein is at least stable under ordinary stability conditions with respect to purity, storage and is free flowing powder. The process is simple, cost-effective, eco-friendly and commercially viable.